Introduction and methods

Although the implementation of guideline-recommended treatment for heart failure with reduced ejection fraction (HFrEF) has resulted in a decline of HF mortality, hospital readmission rates remain high. A recent meta-analysis by Burnett et al (Circ Heart Fail 2017) studied drug treatment for HFrEF in relation to all-cause mortality, but this analysis did not include all currently recommended pharmacological options, and the impact of therapy on hospitalization rates was not assessed.

Therefore, this network analysis aimed to assess the efficacy of all guideline-recommended drug classes on the following major outcomes: all-cause mortality (ACM), CV mortality, all-cause hospitalization and hospitalization for HF (HFH). 58 randomized clinical trials (RCTs) conducted in HFrEF patients reported ACM, and 28 RCTs reported HFH. The network analysis used a random-effects model to consider the relative efficacy of each treatment class or combination of classes on the rates of the four outcomes. The network analysis not only allows direct comparison between trials, but also of other treatments to placebo.

Main results

When arranging treatments from old to new, the most recent showed the most favorable ACM hazard ratio (HR) vs placebo.

Conclusions

These analyses demonstrate that the combination of disease-modifying medications, i.e. ACEI, ARB, BB, MRAs, ivabradine and ARNI, resulted in a progressive improvement in mortality and hospitalization outcomes in HFrEF over the past 30 years. The two most effective combinations for the outcomes studied here, were ARNI+BB+MRA and ACEI+BB+MRA+IVA. Thus, these data underscore the benefit of incremental use of disease-modifying therapies, and support the current international guideline recommendations for the management of HFrEF.

A limitation of this analysis may be that, since 30 years have passed since the oldest and most recent trials included in this study, the profile and the environment of patients enrolled in these trials may have changed substantially. It should be noted that some small, short-term studies with higher mortality rates were included in this meta-analysis, which may have introduced spurious information.

Discussion

Discussant M. Lainscak (Murska Sobota, SI) noted that this is the most comprehensive analysis of its type to date. The first message he sees in the data is that escalation or intensification of therapy yields a lower chance of mortality. Monotherapy is less effective, if effective at all. Secondly, effectiveness of the therapy combinations differ across the outcomes studied. This may be because patients are also often hospitalized for non-HF causes.

The question is how we can translate this into clinical practice, as we do not apply guideline recommendations as we should. We do not always give combination therapy as recommended, possibly to concerns about side-effects, patient preference, but also physician’s inertia can be blamed. Nowadays, the risk of hyperkalemia can be mitigated with potassium-binders, thereby facilitating life-saving therapy. Still, some patients do not want to take many drugs, which raises the question which drug to remove first in a safe way? This important question cannot be answered at present, due to a lack of data.

The main message conveyed by this meta-analysis is that we have advanced a lot in 30 years. Subgroup analysis, eg in patients with diabetes, will yield even more relevant insights.

Our reporting is based on the information provided at the ESC Heart Failure 2018 congress